Streptogramin derivatives, their preparation and compositions which contain them

ABSTRACT

Group A streptogramin derivatives of formula (I) and salts thereof: 
                 
 
and Group A streptogramin derivatives of formula (III) and salts thereof: 
                 
 
as well as processes for preparing such streptogramins, and pharmaceutical compositions comprising such streptogramins, alone or combined with at least one group B streptogramin derivative.

This is a division of application Ser. No. 10/024,186, filed Dec. 21,2001, now U.S. Pat. No. 6,596,717, and claims the benefit of U.S.Provisional Application No. 60/262,645, filed Jan. 22, 2001, all ofwhich are incorporated herein by reference.

Under the provisions of Section 119 of 35 U.S.C., Applicants herebyclaim the benefit of French Application No. 00/16803, filed Dec. 21,2000, which is incorporated herein by reference.

The present invention relates to group A streptogramin derivatives offormula (I):

which have advantageous antibacterial activity.

Among the known streptogramins, pristinamycin (RP 7293), anantibacterial agent of natural origin produced by Streptomycespristinaespiralis, was isolated for the first time in 1955. Thepristinamycin sold under the name Pyostacine® comprises mainlypristinamycin IIA combined with pristinamycin IA.

Another antibacterial agent of the streptogramin class, virginiamycin,was isolated from Streptomyces virginiae, ATCC 13161 [Antibiotics andChemotherapy, 5, 632 (1955)]. Virginiamycin (Staphylomycine®) comprisesmainly factor M₁ (VM1) combined with factor S (VS).

F. Le Goffic et. al., Transformations of Pristinamycin II to Study ItsMechanism of Action, 16(1) Eur. J. Medicinal Chemistry 69(January-February 1981), have disclosed the preparation of dihydroxyderivatives of pristinamycin IIA.

Great Britain patent application GB-A-2 206 879 discloses modified groupA streptogramin derivatives of structure:

wherein:

-   -   R is a substituted alkyl radical or a heterocyclic radical and    -   n is 1 or 2,        however, these derivatives show no activity orally.

The inventors have now found that the group A streptogramin derivativesof formula (I):

wherein:

-   -   R₁ is chosen from alkyl groups, alkenyl groups, alkynyl groups        which may be mono- or polyfluoro groups, C₃-C₆ cycloalkyl        groups, a phenylmethyl group, and heterocyclylmethyl groups,        wherein said heterocyclyl portion is aromatic,    -   R₂ is chosen from a hydrogen atom, a methyl group, and an ethyl        group,    -   the bond        is a single bond (27R stereochemistry) or a double bond,    -   unless otherwise stated, the alkyl groups are chosen from        straight and branched C₁-C₆ alkyl groups,    -   unless otherwise stated, the alkenyl groups are chosen from        straight and branched C₃-C₆ alkenyl groups, and    -   unless otherwise stated, the alkynyl groups are chosen from        straight and branched C₃-C₆ alkynyl groups, have advantageous        antibacterial activity, alone or when combined with at least one        group B streptogramin derivative.

In one embodiment of the invention, for example, when R₁ is aheterocyclylmethyl group, the heterocyclyl portion can, for example, bechosen from a pyrrolyl group, a furyl group, a thienyl group, animidazolyl group, and a pyridyl group.

In one embodiment of the invention, for example, when R₁ is chosen fromalkyl groups mono- or polysubstituted with a fluorine atom, the alkylgroups can, for example, be chosen from C₁ and C₂ alkyl groups.

In another embodiment, for example, R₁ can be chosen from alkenylgroups, such as, an allyl group. In yet another embodiment, R₁ can bechosen from alkynyl groups, such as, for example, a propargyl group.

The streptogramin derivatives of formula (I) may be prepared, forexample, by:

-   -   (a) reacting, in the presence of a phase-transfer agent, a        derivative of formula (IIa):        R₁—X  (IIa)        wherein:    -   R₁ is chosen from alkyl groups, alkenyl groups, alkynyl groups        which may be mono- or polyfluoro groups, C₃-C₆ cycloalkyl        groups, a phenylmethyl group, and heterocyclylmethyl groups,        wherein said heterocyclyl portion is aromatic, and    -   X is chosen from halogen atoms, a methylsulphonyloxy group, a        p-toluenesulphonyloxy group, and a trifluoromethylsulphonyloxy        group,    -   with a dihydroxy streptogramin derivative of formula (II):        wherein:    -   R₂ is chosen from a hydrogen atom, a methyl group, and an ethyl        group,    -   the bond        is a single bond (27R stereochemistry) or a double bond, and    -   (b) optionally protecting with a protecting group, prior to said        reacting, the hydroxyl function in position 14, and then, where        appropriate, removing said protecting group from position 14,        and    -   (c) optionally protecting with a protecting group, prior to said        reacting, the amide function in position 8, and then, where        appropriate, removing said protecting group from position 8.

In one embodiment of the invention, for example, when X is chosen fromhalogen atoms, a derivative of formula (IIa), wherein X is chosen from abromine atom and an iodine atom, can be used for said reacting.

The phase-transfer agent can, for example, be chosen from quaternaryammonium derivatives, for example, salts of tetraalkylammonium and saltsof trialkylbenzylammonium, such as, chloride, bromide, and sulphatesalts.

Said reacting can, for example, be carried out in a basic medium, suchas, for example, a basic medium comprising at least one agent chosenfrom sodium hydroxide, potassium hydroxide, potassium carbonate, andcaesium carbonate.

Said reacting can also, for example, be carried out in anaqueous-organic medium, such as, for example, an aqueous-organic mediumcomprising at least one agent chosen from hydrocarbons (for example,toluene), halogenated solvents (for example, dichloromethane), andesters (for example, ethyl acetate).

Said reacting can, for example, take place at a temperature ranging, forexample, from 10° C. to 60° C., such as, for example, at about 20° C.

The process, for example, can also be performed in the presence of anexcess of the derivative of formula (IIa).

The protection and deprotection of the hydroxyl radical in position 14and of the amide radical in position 8 can be carried out according toknown, art-recognized methods which do not affect the rest of themolecule, such as, for example, by applying the methods described by T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2ndedition), A. Wiley—Interscience Publication (1991) or by Mc Omie,Protective Groups in Organic Chemistry, Plenum Press (1973). Forexample, the protection of the hydroxyl radical in position 14 can becarried out with an allyl protecting group which can be installed andremoved by analogy with the methods described below in the examples. Theprotection of the amide in position 8 may, for example, be carried outwith a t-butoxycarbonyl protecting group.

When the reaction leads to a mixture of the 14- and 16-O-alkyl isomers,these isomers may be separated according to known, art-recognizedmethods which do not affect the rest of the molecule, such as, forexample, by chromatography, i.e., high performance liquid chromatography(HPLC) on a normal or reverse phase, on a chiral or non-chiral phase, orby flash chromatography, by crystallization, or by any other appropriateseparation technique known in the art.

According to the invention, the streptogramin derivatives of formula (I)may also be prepared, for example, by a process comprising:

-   -   (a) desilylation of a silyl and 14-O-allyl derivative of formula        (III):        wherein:        -   R₂ is chosen from a hydrogen atom, a methyl group, and an            ethyl group,        -   the bond            is a single bond (27R stereochemistry) or a double bond,        -   R₃ is a protecting group, and        -   R₄ is a silyl group,    -   (b) 37-O-alkylation of the product obtained in (a) above, and    -   (c) removal of the 14-O-allyl group and the R₃ protecting group        according to known methods which do not affect the rest of the        molecule.

In one embodiment of the invention, the protecting group R₃ can, forexample, be a t-butoxycarbonyl group.

Representative R₄ silyl groups include, for example, trialkylsilylgroups, dialkylphenylsilyl groups, and alkyldiphenyisilyl groups, forexample, a t-butyldiphenylsilyl group and a t-butyldimethylsilyl group.

The desilylation, for example, can be carried out according to known,art-recognized methods which do not affect the rest of the molecule. Theprocess can, for example, be performed in the presence of a source offluoride ions, such as, for example, tetra-n-butylammonium fluoride or,for example, a hydrofluoric acid/amine complex, wherein the amine, forexample, can be an amine chosen from triethylamine and pyridine. Thereaction, for example, can be carried out in a chlorinated solvent (forexample, dichloromethane) or in an ether (for example, tetrahydrofuran)at a temperature ranging, for example, from 20° C. to 80° C.

The 37-O-alkylation reaction, for example, can be carried out byreacting a derivative of formula (IIa) as defined above, with thedesilylated streptogramin of formula (III). This process can beperformed under an inert atmosphere (for example, under nitrogen orargon), in basic medium, for example, in the presence of sodium hydride,alkali metal (for example, lithium, sodium, or potassium)hexamethyldisilylamide, or in the presence of an organolithium reagent(for example, n-butyllithium), or alternatively in the presence of anamide (for example, lithium diisopropylamide), in an inert solvent suchas an amide (for example, dimethylformamide) or an ether (for example,tetrahydrofuran), at a temperature ranging, for example, from −20° C. to60° C.

Removal of the allyl group can be carried out, for example, in thepresence of a proton donor such as 4-methylphenylsulphinic acid, in thepresence of a palladium catalyst, for example,tetrakis(triphenylphosphine)-palladium, in a chlorinated solvent, forexample, dichloromethane, at a temperature ranging, for example, from 0°C. to 60° C. It is also possible to perform the process according to themethods described in the references cited above. The t-butoxycarbonylgroup can, for example, be removed according to known methods which donot affect the rest of the molecule, such as, for example, in a solventsuch as dimethyl sulphoxide, dimethylformamide or diphenyl ether, at atemperature ranging, for example, from 130° C. to 170° C.

The streptogramin derivative of formula (III) may be prepared, forexample, by 36-O-allylation and then 37-O-silylation and protection ofthe amide in position 8 with a radical R₃, and where appropriateoptionally removing the protecting group R₃.

The 36-O-allylation can be carried out according to known,art-recognized methods, such as, for example, those cited in the abovereferences. For example, the 36-O-allylation may be carried out byreacting an allyl halide (for example, bromide) or a methylsulphonyloxyderivative, p-toluenesulphonyloxy derivative, or atrifluoromethylsulphonyloxy derivative in the presence of a base, suchas a carbonate (for example, potassium carbonate or caesium carbonate),in a solvent, such as a ketone (for example, methyl ethyl ketone), anitrile (for example, acetonitrile) or a hydrocarbon (for example,toluene), at a temperature ranging, for example, from 40° C. to 80° C.,such as, for example, about 70° C.

The silylation may be carried out, for example, according to known,art-recognized methods which do not affect the rest of the molecule,such as by using a halide (for example, a chloride) of the silyl groupR₄. For example, the process can be performed using trialkylsilylchloride, dialkylphenylsilyl chloride or alkyldiphenylsilyl chloride(for example, t-butyldiphenylsilyl chloride or t-butyldimethylsilylchloride), working in a solvent, such as a chlorinated solvent (forexample, dichloromethane), an amide (for example, dimethylformamide), anether (for example, tetrahydrofuran), or a nitrile (for example,acetonitrile), at a temperature ranging, for example, from 0° C. to 60°C., such as, for example, at about room temperature.

The installation of the protecting group R₃ can be carried out, forexample, according to the methods mentioned above. For example, it canbe carried out in the presence of an excess of di-t-butyl dicarbonate, abase (triethylamine or pyridine) and optionally a catalyst, such as4-dimethylaminopyridine, in a chlorinated solvent (dichloromethane) oran ether (tetrahydrofuran) at a temperature ranging, for example, from0° C. to 80° C.

For example, the dihydroxylated group A streptogramin derivative offormula (II) may be obtained by:

-   (a) selective reduction of a natural pristinamycin component of    formula (IV):    wherein;    -   R₂ is chosen from a hydrogen atom, a methyl group, and an ethyl        group, and    -   the bond        is a single bond (27R stereochemistry) or a double bond, and-   (b) separation of the 16S epimer form.

The reduction can be carried out, for example, in the presence of areducing agent, such as an alkali metal borohydride, for example, sodiumborohydride or sodium triacetoxyborohydride, in an organic solventchosen from chlorinated solvents (for example, dichloromethane,dichloroethane or chloroform), tetrahydrofuran, acetic acid and alcoholssuch as methanol, ethanol or 2-propanol, at a temperature ranging, forexample, from −78° C. to 40° C.

The separation of the 16R epimer form and of the 16S epimer form can becarried out, for example, according to known, art-recognized methods.For example, the separation of the epimer forms may be carried out bychromatography, flash chromatography, high performance liquidchromatography (HPLC), on a chiral or non-chiral phase, or centrifugalpartition chromatography (CPC), starting with the mixture of the 16R and16S epimers. Further, the separation may be carried out bycrystallization, or by any other appropriate separation techniqueavailable in the art.

The pristinamycin derivatives of formula (IV) correspond, respectively,to pristinamycin IIA (PIIA), pristinamycin IIB (PIIB), pristinamycin IIC(PIIC), pristinamycin IID (PIID), pristinamycin IIF (PIIF), andpristinamycin IIG (PIIG), which are known components of naturalpristinamycin. The components PIIF and PIIG have been disclosed inEuropean patent application no. EP-A-0 614 910. Pristinamycin IIC (PIIC)and pristinamycin IID (PIID) may be obtained as described by J. C.Barrière et al., Expert. Opin. Invest. Drugs, 3(2), 115-31 (1994).

The present invention also relates to pristinamycin derivatives offormula (III), which are novel products.

The preparation and separation of the natural group A streptogramincomponents [streptogramins of formula (IV)] can be carried out, forexample, by fermentation and isolation of the constituents from thefermentation must according to or by analogy with the method describedby J. Preud'homme et al., Bull. Soc. Chim. Fr., vol. 2, 585 (1968), orin European patent application no. EP-A-0 614 910. Additionally, thepreparation of natural group A components may be carried out, forexample, by specific fermentation, as disclosed in French patentapplication no. FR-A-2 689 518.

The streptogramin derivatives of formula (I) may be purified, whereappropriate, by physical methods such as crystallization, chromatographyand Centrifugal Partition Chromatography (CPC).

The streptogramin derivatives according to the present invention havesuperior antibacterial properties and synergistic properties withrespect to the antibacterial activity of the group B streptograminderivatives. They are notably advantageous on account of their powerfulactivity, alone or in combination.

When at least one group A streptogramin derivative of the invention iscombined with at least one group B streptogramin component orderivative, this component or derivative may be chosen, depending onwhether it is desired to obtain a form for oral or parenteraladministration, from natural group B streptogramin components, such as,for example, pristinamycin IA, pristinamycin IB, pristinamycin IC,pristinamycin ID, pristinamycin IE, pristinamycin IF, pristinamycin IG,virginiamycin S1, S3 or S4, vernamycin B or C, etamycin, and fromsemisynthetic derivatives as disclosed in U.S. Pat. Nos. or Europeanpatent application nos. U.S. Pat. Nos. 4,618,599, 4,798,827, 5,326,782,EP-A-0 772 630 and EP-A-0 770 132.

Representative group B streptogramin components and derivatives mayinclude, for example, (I) streptogramin derivatives of formula (A), andsalts thereof:

wherein:

-   (1) Rb, Rc, Re, and Rf are each a hydrogen atom;    -   Rd is chosen from a hydrogen atom and a dimethylamino group; and    -   Ra is chosen from:        -   (A) —CH₂R′a groups, wherein R′a is chosen from:            -   (i) a pyrrolidinyl-3-thio group,            -   (ii) a piperidyl-3-thio group,            -   (iii) a piperidyl-4-thio group,                -   wherein said groups (i)-(iii) may be unsubstituted                    or substituted with at least one group chosen from                    alkyl groups, and            -   (iv) alkylthio groups which are substituted with 1 or 2                groups chosen from:                -   (a) a hydroxysulfonyl group,                -   (b) alkylamino groups,                -   (c) dialkylamino groups, which may be unsubstituted                    or substituted with at least one group chosen from a                    mercapto group or dialkylamino groups,                -   (d) a piperazine ring which may be substituted or                    unsubstituted, a morpholino group, a thiomorpholino                    group, a piperidino group, a 1-pyrrolidinyl group, a                    2-piperidyl group, a 3-piperidyl group, a                    4-piperidyl group, a 2-pyrrolidinyl group, and a                    3-pyrrolidinyl group, each of which may be                    unsubstituted or substituted with alkyl, and        -   (B) ═CHR′a groups, wherein R′a is chosen from:            -   (i) a pyrrolidinyl-3-amino group,            -   (ii) a piperidyl-3-amino group and a piperidyl-4-amino                group,            -   (iii) a pyrrolidinyl-3-oxy group,            -   (iv) a piperidyl-3-oxy group and a piperidyl-4-oxy                group,            -   (v) a pyrrolidinyl-3-thio group,            -   (vi) a piperidyl-3-thio group and a piperidyl-4-thio                group,                -   wherein said groups (i)-(vi) may be unsubstituted or                    substituted with at least one group chosen from                    alkyl groups,            -   (vii) alkylamino groups,            -   (viii) alkyloxy groups, and            -   (ix) alkylthio groups,            -   wherein said groups (vii), (viii), and (ix) are                substituted with 1 or 2 groups chosen from:                -   (a) a hydroxysulfonyl group,                -   (b) alkylamino groups,                -   (c) dialkylamino groups unsubstituted or substituted                    with at least one group chosen from dialkylamino                    groups,                -   (d) trialkylammonio groups,                -   (e) a 4-imidazolyl group, and a 5-imidazolyl group,                    each of which may be unsubstituted or substituted                    with alkyl,                -   (f) a piperazine ring which may be substituted or                    unsubstituted, a morpholino group, a thiomorpholino                    group, a piperidino group, a 1-pyrrolidinyl group, a                    2-piperidyl group, a 3-piperidyl group, a                    4-piperidyl group, a 2-pyrrolidinyl group, and a                    3-pyrrolidinyl group, each of which may be                    unsubstituted or substituted with alkyl,        -   (C) a quinuclidinyl-3-thiomethyl group, and        -   (D) a quinuclidinyl-4-thiomethyl group; or    -   (2) —Ra is a hydrogen atom, and        -   (a) —Rb, Re, and Rf are each a hydrogen atom, and            -   Rd is chosen from a —NHCH₃ group and a —N(CH₃)₂ group,                and Rc is chosen from a chlorine atom and a bromine                atom, or, when Rd is a —N(CH₃)₂ group, Rc is chosen from                (C₃-C₅) alkenyl groups, or        -   (b) —Rb, Rd, Re, and Rf are each a hydrogen atom, and            -   Rc is chosen from halogen atoms, aminomonoalkyl groups,                aminodialkyl groups, alkyloxy groups, a                trifluoromethyloxy group, thioalkyl groups, (C₁-C₃)                alkyl groups, and trihalomethyl groups, or        -   (c) —Rb, Rc, Re, and Rf are each a hydrogen atom, and            -   Rd is chosen from halogen atoms, an ethylamino group, a                diethylamino group, a methylethylamino group, alkyloxy                groups, a trifluoromethyloxy group, thioalkyl groups,                (C₁-C₆) alkyl groups, aryl groups, and trihalomethyl                groups, or        -   (d) —Rb, Re, and Rf are each a hydrogen atom,            -   Rc is chosen from halogen atoms, aminomonoalkyl groups,                aminodialkyl groups, alkyloxy groups, a                trifluoromethyloxy group, thioalkyl groups, and (C₁-C₃)                alkyl groups, and            -   Rd is chosen from halogen atoms, an amino group,                aminomonoalkyl groups, aminodialkyl groups, alkyloxy                groups, a trifluoromethyloxy group, thioalkyl groups,                (C₁-C₆) alkyl groups, and trihalomethyl groups, or        -   (e) —Rc, Re, and Rf are each a hydrogen atom, and            -   Rb and Rd are each a methyl group,                and further, for example, (II) semisynthetic group B                streptogramin derivatives of formula (B), and salts                thereof:                wherein:-   (A) Y is chosen from (i) a nitrogen atom and (ii) ═CR₃— groups, and    -   (1) when Y is chosen from ═CR₃— groups, R₁ is chosen from        -   (a₁) a hydrogen atom, C₁-C₈ alkyl groups, and C₂-C₈ alkenyl            groups,        -   (b₁) C₃-C₈ cycloalkyl groups, and saturated and unsaturated            3- to 8-membered heterocyclyl groups,        -   (c₁) an unsubstituted phenyl group,        -   (d₁) a phenyl group substituted with at least one            substituent chosen from halogen atoms, a hydroxyl group,            alkyl groups, alkyloxy groups, alkylthio groups,            alkylsulphinyl groups, alkylsulphonyl groups, an amino            group, alkylamino groups, and dialkylamino groups, and        -   (e₁)groups —NR′R″, wherein:        -   R′ and R″, which are identical or different, are each chosen            from a hydrogen atom, and C₁-C₃ alkyl groups, or        -   R′ and R″, form, together with the nitrogen atom to which            they are attached, a 3- to 8-membered heterocyclyl group,            wherein one of said members, in addition to said nitrogen            atom, may be a heteroatom chosen from an oxygen atom, a            sulphur atom, and a nitrogen atom, and wherein said            heterocyclyl group is unsubstituted or substituted with a            group chosen from alkyl groups, C₂-C₈ alkenyl groups, C₃-C₆            cycloalkyl groups, saturated and unsaturated 4- to            6-membered heterocyclyl groups, a benzyl group, an            unsubstituted phenyl group, and a substituted phenyl group,            as defined above in (d₁),        -   (f₁) halomethyl groups, a hydroxymethyl group, and            alkyloxymethyl groups,        -   (g₁) alkylthiomethyl groups, wherein said alkyl portion is            unsubstituted or substituted with an —NR′R″ group, and            wherein said R′ and said R″ are as defined above in (e₁),        -   (h₁) alkylsulphinylmethyl groups, alkylsulphonylmethyl            groups, an acyloxymethyl group, a benzoyloxymethyl group, a            cyclopropylaminomethyl group, and —(CH₂)_(n)NR′R″ groups,            wherein n is chosen from integers ranging from 1 to 4, and            wherein said R′ and said R″ are as defined above in (e₁),            and        -   (i₁) when R₃ is a hydrogen atom, R₁ is additionally chosen            from a formyl group, a carboxyl group, alkyloxycarbonyl            groups, and            -   —CONR′R″ groups, wherein said R′ and said R″ are defined                as above in (e₁), and    -   (2) when Y is a nitrogen atom, R₁ is chosen from        -   (a₂)options (a₁), (b₁), (c₁), (d₁), and (e₁) as defined            above, and        -   (b₂) XR^(o) groups, wherein X is chosen from an oxygen atom,            a sulphur atom, a sulphinyl group, a sulphonyl group, and an            —NH— group, and wherein R^(o) is chosen from (i) (C₁ to C₈)            alkyl groups, (ii) (C₃ to C₆) cycloalkyl groups, (iii)            saturated and unsaturated 3- to 8-membered heterocyclyl            groups, (iv) 3- to 8-membered heterocyclylmethyl groups in            which the heterocyclyl portion is attached to the methyl            group by a carbon atom, (v) an unsubstituted phenyl            group, (vi) phenyl groups substituted with at least one            group chosen from halogen atoms, a hydroxyl group, alkyl            groups, alkyloxy groups, alkylthio groups, alkylsulfinyl            groups, alkylsulfonyl groups, an amino group, alkylamino            groups, and dialkylamino groups, (vii) —(CH₂)_(n)NR′R″            groups, wherein R′ and R″ are as defined above in (e₁), and            wherein n is chosen from integers ranging from 2 to 4,            and (viii) if X is an NH group, R^(o) may also be a hydrogen            atom;-   (B) R₂ is chosen from a hydrogen atom and C₁-C₃ alkyl groups,-   (C) R₃ is chosen from a hydrogen atom, alkyl groups, a carboxyl    group, alkyloxycarbonyl groups, and carbamoyl groups of formula    —CO—NR′R″, wherein said R′ and said R″ are defined as above in (e₁),-   (D) Ra is chosen from a methyl group and an ethyl group, and-   (E) Rb, Rc, and Rd are defined as follows:    -   (1) —Rb and Rc are each a hydrogen atom and        -   Rd is chosen from a hydrogen atom, a methylamino group, and            a dimethylamino group, or    -   (2) —Rb is a hydrogen atom,        -   Rc is chosen from a hydrogen atom, a chlorine atom, a            bromine atom, and C₃-C₅ alkenyl groups, and        -   Rd is chosen from —N(CH₃)R′″ groups, wherein        -   R′″ is chosen from            -   (a) alkyl groups,            -   (b) C₂-C₄ hydroxyalkyl groups,            -   (c) C₂-C₈ alkenyl groups, wherein said C₂-C₈ alkenyl                groups are unsubstituted or substituted with (i) an                unsubstituted phenyl group, (ii) a                cycloalkyl(C₃-C₆)methyl group, (iii) an unsubstituted                benzyl group, (iv) a benzyl group substituted with at                least one substituent chosen from halogen atoms, a                hydroxyl group, alkyl groups, alkyloxy groups, alkylthio                groups, alkylsulphinyl groups, alkylsulphonyl groups, an                amino group, alkylamino groups, and dialkylamino groups,                or (v) heterocyclylmethyl groups and heterocyclylethyl                groups, wherein said heterocyclyl portions of said                heterocyclylmethyl groups and said heterocyclylethyl                groups are chosen from saturated and unsaturated 5- to                6-membered heterocyclyl groups comprising from 1 to 2                heteroatoms chosen from a sulphur atom, an oxygen atom,                and a nitrogen atom, and wherein said heterocyclyl                groups may be unsubstituted or substituted with a group                chosen from alkyl groups, C₂-C₈ alkenyl groups, C₃-C₆                cycloalkyl groups, saturated and unsaturated 4- to                6-membered heterocyclyl groups, an unsubstituted phenyl                group, a benzyl group, or a substituted phenyl group as                defined above in (d₁),            -   (d) a cyanomethyl group,            -   (e) —CH₂CORe groups, wherein Re is chosen from (i) —OR′e                groups, wherein R′e is chosen from a hydrogen atom,                C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, a benzyl                group, and heterocyclylmethyl groups, wherein said                heterocyclyl portion is chosen from 5- to 6- membered                heterocyclyl groups comprising from 1 to 2 heteroatoms                chosen from a sulphur atom, an oxygen atom, and a                nitrogen atom, (ii) alkylamino groups, alkylmethylamino                groups, heterocyclylamino groups and                heterocyclylmethylamino groups, wherein said                heterocyclyl portion of said heterocyclylamino groups                and said heterocyclylmethylamino groups is chosen from                5- to 6- membered saturated heterocyclyl groups                comprising from 1 to 2 heteroatoms chosen from a sulphur                atom, an oxygen atom, and a nitrogen atom, and wherein                said heterocyclyl groups may be unsubstituted or                substituted with a group chosen from alkyl groups, a                benzyl group, and alkyloxycarbonyl groups, or    -   (3) Rb is a hydrogen atom,        -   Rd is chosen from an —NHCH₃ group and an —N(CH₃)₂ group, and        -   Rc is chosen from a chlorine atom, and a bromine atom, and            when Rd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅            alkenyl groups, or    -   (4) —Rb and Rd are each a hydrogen atom, and        -   Rc is chosen from halogen atoms, alkylamino groups,            dialkylamino groups, alkyloxy groups, a trifluoromethoxy            group, thioalkyl groups, C₁-C₆ alkyl groups, and            trihalomethyl groups, or    -   (5) —Rb and Rc are each a hydrogen atom, and        -   Rd is chosen from halogen atoms, an ethylamino group, a            diethylamino group, a methylethylamino group, alkyloxy            groups, a trifluoromethoxy group, alkylthio groups,            alkylsulphinyl groups, alkylsulphonyl groups, C₁-C₆ alkyl            groups, a phenyl group, and trihalomethyl groups, or    -   (6) —Rb is a hydrogen atom, and        -   Rc is chosen from halogen atoms, alkylamino groups,            dialkylamino groups, alkyloxy groups, a trifluoromethoxy            group, thioalkyl groups, and C₁-C₃ alkyl groups, and        -   Rd is chosen from halogen atoms, an amino group, alkylamino            groups, dialkylamino groups, alkyloxy groups, a            trifluoromethoxy group, thioalkyl groups, C₁-C₆ alkyl            groups, and trihalomethyl groups, or    -   (7) Rc is a hydrogen atom, and        -   Rb and Rd are each a methyl group, and even further, for            example, (III) semisynthetic group B derivatives of formula            (C), and salts thereof, when salts exists:            wherein:-   (A) R is chosen from    -   (1) —NR₁R₂ groups, wherein R₁ and R₂, which may be identical or        different, are each chosen from        -   (i) a hydrogen atom,        -   (ii) (C₁-C₈) alkyl groups,        -   (iii) (C₁-C₈) alkyl groups substituted with a hydroxyl            group,        -   (iv) (C₃-C₈) alkenyl groups,        -   (v) (C₃-C₈) cycloalkyl groups,        -   (vi) (C₁-C₈) alkyloxy groups,        -   (vii) dialkylamino groups,        -   (viii) phenylalkyl groups,        -   (ix) phenylalkyl groups substituted with at least one group            chosen from halogen atoms, alkyl groups, hydroxyalkyl            groups, alkyloxy groups, and dialkylamino groups, and        -   (x) 3- to 8-membered saturated and unsaturated            heterocyclylalkyl groups comprising at least one hetero atom            chosen from nitrogen, oxygen, and sulphur, or        -   (xi) R₁ and R₂ form, together with the nitrogen atom to            which they are attached, a saturated, partially saturated or            unsaturated mono- or polycyclic 3- to 12-membered            heterocycle group, wherein one of said members, in addition            to said nitrogen atom, may be an atom chosen from oxygen,            sulphur, and nitrogen, and wherein said heterocyclyl group            is unsubstituted or substituted with at least one group            chosen from a hydroxyl group, alkyl groups, an unsubstituted            phenyl group, a phenyl group substituted with a halogen            atom, phenylalkyl groups, phenyl(C₂-C₄)alkenyl groups,            hydroxyalkyl groups, acyl groups, alkyloxycarbonyl groups,            heterocyclyl groups and heterocyclylcarbonyl groups, wherein            the heterocyclyl portion is saturated or unsaturated (4- to            6-membered) and comprises at least one hetero atom chosen            from nitrogen, sulphur, and oxygen, and    -   (2) —SR₃ groups, wherein R₃ is chosen from        -   (i) (C₁-C₈) alkyl groups and(C₃-C₈) cycloalkyl groups            substituted with —NR₁R₂, wherein R₁ and R₂, which may be            identical or different, are each chosen from a hydrogen atom            and alkyl groups, or form, together with the nitrogen atom            to which they are attached, a heterocycle as defined in (xi)            above, and        -   (ii) saturated and unsaturated heterocyclyl and            heterocyclylmethyl (3- to 7-membered) groups, wherein one of            said members, in addition to said nitrogen atom, may be an            atom chosen from oxygen, sulphur, and nitrogen, and wherein            said heterocyclyl portion is unsubstituted or substituted            with an alkyl group,-   (B)    is a residue of an unsaturated ring which is not substituted in the    5γ position    or the residue of a saturated ring which is substituted in the 5γ    position with a fluorine atom-   (C) Ra is chosen from a methyl group and an ethyl group, and-   (D) Rb, Rc and Rd are defined below:    -   1) Rb and Rc are each a hydrogen atom, and Rd is chosen from a        hydrogen atom, a methylamino group, and a dimethylamino group,        or    -   2) Rb is a hydrogen atom, Rc is chosen from a hydrogen atom, a        chlorine atom, a bromine atom, and a (C₃ to C₅) alkenyl group,        and Rd is —N(CH₃)—R′″, wherein R′″ is chosen from:        -   (1) alkyl groups, (2) (C₂ to C₄) hydroxyalkyl groups, (3)            (C₂ to C₈) alkenyl groups, (4) phenylalkenyl groups, (5)            cycloalkyl(C₃ to C₆)methyl groups, (6) an unsubstituted            benzyl group, (7) a substituted benzyl group, (8)            heterocyclylmethyl groups and heterocyclylethyl groups, (9)            a —CH₂CN group, (10) a —CH₂COOH group, and (11) —CORe groups            and —CH₂CORe groups for which either:            -   (a) Re is —OR′e, wherein R′e is chosen from a hydrogen                atom, C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, a benzyl                group, and heterocyclylmethyl groups, wherein said                heterocyclyl portion is chosen from 5- to 6-membered                heterocyclyl groups comprising from 1 to 2 heteroatoms                chosen from a sulphur atom, an oxygen atom, and a                nitrogen atom, or            -   (b) Re is chosen from alkylamino groups,                alkylmethylamino groups, heterocyclylamino groups, and                heterocyclylmethylamino groups, or    -   3) Rb is a hydrogen atom,        -   Rd is chosen from an —NHCH₃ group and an —N(CH₃)₂ group, and        -   Rc is chosen from a chlorine atom, and a bromine atom, and            when Rd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅            alkenyl groups, or    -   4) Rb and Rd are each a hydrogen atom, and Rc is chosen from        halogen atoms, alkylamino groups, dialkylamino groups, alkyloxy        groups, a trifluoromethoxy group, thioalkyl groups, (C₁-C₆)        alkyl groups, and trihalomethyl groups, or    -   5) Rb and Rc are each a hydrogen atom, and Rd is chosen from        halogen atoms, an ethylamino group, a diethylamino group, a        methylethylamino group, alkyloxy groups, a trifluoromethoxy        group, alkylthio groups, alkylsulphinyl groups, alkylsulphonyl        groups, (C₁-C₆) alkyl groups, a phenyl group, and trihalomethyl        groups, or    -   6) Rb is a hydrogen atom, Rc is chosen from halogen atoms,        alkylamino groups, dialkylamino groups, alkyloxy groups, a        trifluoromethoxy group, thioalkyl groups, (C₁-C₃) alkyl groups,        and Rd is chosen from halogen atoms, an amino group, alkylamino        groups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy        group, thioalkyl groups, (C₁-C₆) alkyl groups, and trihalomethyl        groups, or    -   7) Rc is a hydrogen atom, and Rb and Rd are each a methyl group.

It is understood that the combinations formed from the derivativesaccording to the invention and from group B streptogramins also fallwithin the context of the present invention.

The group B streptogramin derivatives of formula (B) may be prepared,for example, according to the methods disclosed in International patentapplication no. PCT/FR 99/00409. The group B streptogramin derivativesof formula (C) may be prepared, for example, according to the methodsdisclosed in International patent application no. PCT/FR 00/02146.

In vitro on Staphylococcus aureus IP8203, the streptogramin derivativesaccording to the invention have been shown to be active atconcentrations ranging, for example, from 0.06 to 32 μg/ml, alone orcombined with at least one group B derivative such as pristinamycin IB.In vivo, the streptogramin derivatives according to the inventionsynergized the antimicrobial activity of pristinamycin I_(B) onexperimental infections of mice with Staphylococcus aureus IP8203 atdoses ranging, for example, from 32 to 150 mg/kg orally (DC₅₀).

Representative streptogramin derivatives of formula (I) include, forexample, streptogramin derivatives of formula (I) wherein:

-   R₁ is chosen from alkyl groups, alkenyl groups, and alkynyl groups,-   R₂ is a methyl group, and-   the bond    is a single bond (27R stereochemistry) or a double bond. The    compounds described below in the Examples are exemplary of such    products.

The compounds according to the invention are advantageous on account oftheir low toxicity. None of the compounds of the invention has shown anytoxicity at doses of 150 mg/kg on Staphylococcus aureus IP8203, whenadministered twice a day subcutaneously or orally in mice.

Representative group A streptogramin derivatives of formula (I), whichmay be used according to the invention, for example, include thecompounds mentioned below in the examples, and the following compounds:

-   (16R)-16-deoxo-16-trifluoromethoxypristinamycin II_(B)-   (16R)-16-deoxo-16-trifluoromethoxypristinamycin II_(A)-   (16R)-16-deoxo-16-difluoromethoxypristinamycin II_(B)-   (16R)-16-deoxo-16-difluoromethoxypristinamycin II_(A)-   (16R)-16-deoxo-16-fluoromethoxypristinamycin II_(B)-   (16R)-16-deoxo-16-fluoromethoxypristinamycin II_(A)-   (16R)-16-deoxo-16-cyclopropyloxypristinamycin II_(B)-   (16R)-16-deoxo-16-cyclopropyloxypristinamycin II_(A)-   (16R)-16-deoxo-16-cyclobutyloxypristinamycin II_(B)-   (16R)-16-deoxo-16-cyclobutyloxypristinamycin II_(A)-   (16R)-16-deoxo-16-isopropyloxypristinamycin II_(B)-   (16R)-16-deoxo-16-isopropyloxypristinamycin II_(A).-   (16R)-16-deoxo-16-(2-fluoropropen-3-yloxy)pristinamycin II_(B)-   (16R)-16-deoxo-16-(2-fluoropropen-3-yloxy)pristinamycin II_(A)

The examples which follow, given without any implied limitation,illustrate the present invention.

In the examples which follow, the 16-deoxopristinamycin IIA (or IIB)nomenclature indicates the replacement of the ketone function inposition 16 with 2 hydrogen atoms. As the chromatography proceeded, allthe fractions were analyzed by thin layer chromatography (TLC) on Merck60F254 silica plates. The fractions corresponding to the same spot onTLC were combined and then concentrated to dryness, under reducedpressure (30° C.; 2.7 kPa). The residues thus obtained were analyzed byknown, art-recognized spectroscopic techniques (NMR; IR; MS), allowingthe expected product to be identified.

EXAMPLE 1

(16R)-16-Deoxo-16-methoxypristinamycin II_(B)

A solution of 0.6 g of(16R)-8-N-tert-butyloxycarbonyl-16-deoxo-16-methoxypristinamycin II_(B)in 15 cm³ of N,N-dimethylformamide was boiled for 2.5 hours. Thereaction mixture was poured into 200 cm³ of ice-cold water and theaqueous phase was then extracted with 3 times 100 cm³ of ethyl acetate.The organic phases were combined, washed with 3 times 200 cm³ ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) to give 0.65 g of a yellow oil, which was purified byflash chromatography on silica [eluent:dichloromethane/methanol/acetonitrile (90/5/5 by volume)]. Afterconcentrating the fractions containing the expected product, 0.16 g of ayellow foam was obtained and was recrystallized from 3 cm³ of hotacetonitrile to give 0.13 g of (16R)-16-deoxo-16-methoxypristinamycinII_(B), in the form of a white powder that melted at about 124° C.(dec.).

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (d, J=6.5 Hz: 3H); 1.00(d, J=6.5 Hz: 3H); 1.08 (d, J=6.5 Hz: 3H); 1.70 (ddd, J=14-7 and 3 Hz:1H); from 1.75 to 2.05 (mt: 5H); 1.82 (s: 3H); 1.89 (d, J=3 Hz: 1H);2.14 (mt: 1H); 2.75 (mt: 1H); 2.80 (dd, J=16 and 8.5 Hz: 1H); 3.18 (dd,J=16 and 3.5 Hz: 1H); 3.45 (s: 3H); 3.50 (mt: 1H); 3.75 (mt: 1H); 3.95(mt: 2H); 4.45 (mt: 1H); 4.70 (mt: 1H); from 4.75 to 4.85 (mt: 2H); 5.37(broad d, J=9 Hz: 1H); 5.72 (ddd, J=16-8 and 4.5Hz: 1H); 5.81 (dd,J=16.5 and 1.5 Hz: 1H); 6.07 (mt: 1H); 6.18 (d, J=16 Hz: 1H); 6.51 (dd,J=16.5 and 5 Hz: 1H); 8.10 (s: 1H).

(16R)-8-N-tert-Butyloxycarbonyl-16-deoxo-16-methoxypristinamycin II_(B)was prepared in the following way:

2.4 cm³ of 1N hydrochloric acid were added, at 0° C. under an argonatmosphere, to a solution of 0.41 g of sodium p-toluenesulphinate in 14cm³ of dichloromethane, and the mixture was then allowed to warm to roomtemperature over 15 minutes. This solution was dried over magnesiumsulphate, filtered and then poured at 20° C., under an argon atmosphere,into a solution of 0.93 g of(16R)-14-O-allyl-8-N-tert-butyloxycarbonyl-16-deoxo-16-methoxypristinamycinII_(B) and 0.31 g of tetrakis(triphenylphosphine)palladium in 18 cm³ ofdichloromethane. After stirring for 30 minutes at room temperature, thereaction mixture was poured into 100 cm³ of water and the phases werethen separated by settling. The organic phase was dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) to give 1.66 g of a yellow oil which was purified byflash chromatography on silica [eluent:dichloromethane/acetonitrile/methanol (95/2.5/2.5 by volume)]. Afterconcentrating the fractions containing the expected product, 0.63 g of ayellow foam was obtained and was stirred in 5 cm³ of pentane and thenfiltered and dried under reduced pressure (2.7 kPa) to give 0.6 g of(16R)-8-N-tert-butyloxycarbonyl-16-deoxo-16-methoxypristinamycin II_(B)in the form of a pale yellow solid.

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (mt: 6H); 1.15 (d,J=6.5Hz: 3H); from 1.35 to 2.15 (mt: 7H); 1.57 (s: 9H); 1.81 (s, 3H);2.41 (d, J=2.5 Hz: 1H); 2.77 (mt: 1H); 2.87 (dd, J=16 and 8 Hz: 1H);3.21 (dd, J=16 and 4Hz; 1H); 3.46 (s: 3H); from 3.70 to 3.95 (mt: 3H);4.12 (broad dd, J=14 and 4.5 Hz: 1H); 4.62 (dd, J=14 and 9 Hz: 1H); 4.72(mt: 1H); 4.81 (dd, J=8 and 2.5 Hz: 1H); 4.89 (dd, J=10 and 2 Hz: 1H);5.52 (broad d, J=9 Hz: 1H); 5.67 (ddd, J=16-9 and 4.5Hz: 1H); 6.28 (d,J=16 Hz: 1H); 6.94 (dd, J=16 and 1.5 Hz: 1H); 7.04 (dd, J=16 and 4 Hz:1H); 8.14 (s: 1H).

(16R)-14-O-Allyl-8-N-tert-butyloxycarbonyl-16-deoxo-16-methoxypristinamycinII_(B) was prepared in the following way:

0.19 cm³ of iodomethane and 0.043 g of 50% sodium hydride in petroleumjelly were added, at 25° C. under an argon atmosphere, to 0.4 g of(16R)-14-O-allyl-8-N-tert-butyloxycarbonyl-16-deoxo-16-hydroxy-pristinamycinII_(B) dissolved in 5 cm³ of N,N-dimethyl-formamide. After stirring for4 hours, the reaction mixture was diluted with 20 cm³ of ethyl acetateand then poured into 40 cm³ of water. The organic phase was separatedout after settling had taken place, and then washed with 40 cm³ ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate, filtered and then concentrated to dryness under reducedpressure (2.7 kPa) to give 0.31 of a yellow oil, which was purified byflash chromatography on silica [eluent:dichloromethane/acetonitrile/methanol (95/2.5/2.5 by volume)]. Afterconcentrating the fractions containing the expected product, 0.06 g of(16R)-14-O-allyl-8-N-tert-butyloxycarbonyl-16-deoxo-16-methoxy-pristinamycinII_(B) was obtained in the form of a white solid.

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (d, J=6.5 Hz: 6H); 1.15(d, J=6.5 Hz: 3H); from 1.40 to 2.15 (mt: 7H); 1.57 (s: 9H); 1.82 (s,3H); 2.78 (mt: 1H); 2.96 (dd, J=16 and 6 Hz: 1H); 3.06 (dd, J=16 and 4Hz: 1H); 3.38 (s: 3H); from 3.70 to 3.85 (mt: 2H); 3.90 (mt: 2H); 3.98(broad dd, J=12 and 5 Hz: 1H); 4.21 (dd, J=15 and 4 Hz: 1H); 4.37 (mt:1H); 4.60 (dd, J=15 and 8.5 Hz: 1H); 4.84 (dd, J=8 and 2.5 Hz: 1H); 4.89(dd, J=10 and 2 Hz: 1H); 5.15 (dd, J=10 and 1 Hz: 1H); 5.24 (dd, J=18and 1 Hz: 1H); 5.35 (broad d, J=9 Hz: 1H); 5.70 (ddd, J=16-8.5 and 4 Hz:1H); 5.89 (mt: 1H); 6.28 (d, J=16 Hz: 1H); 6.98 (d, J=16 Hz: 1H); 7.04(dd, J=16 and 4 Hz: 1H); 8.15(s: 1H).

(16R)-14-O-Allyl-8-N-tert-butyloxycarbonyl-16-deoxo-16-hydroxypristinamycinII_(B) was prepared in the following way:

90 cm³ of triethylamine trihydrofluoride were added to 16.05 g of(16R)-14-O-allyl-16-(tert-butyl-dimethylsilyloxy-8-N-tert-butyloxycarbonyl-16-deoxo-pristinamycinII_(B) dissolved in 80 cm³ of dichloro-methane. After stirring for 17hours at 40° C., the reaction mixture was diluted with 100 cm³ ofdichloro-methane and then poured into 300 cm³ of water. The pH of theaqueous phase was adjusted to 8 by slow addition of sodium bicarbonate.The organic phase was separated out after settling had taken place andthen dried over sodium sulphate, filtered and concentrated to drynessunder reduced pressure (2.7 kPa) to give 16.5 g of a yellow oil, whichwas purified by flash chromatography on silica [eluent:dichloromethane/acetonitrile/methanol (93/3.5/3.5 by volume)]. Afterconcentrating the fractions containing the expected products, 10.23 g of(16R)-14-O-allyl-8-N-tert-butyloxycarbonyl-16-deoxo-16-hydroxypristinamycinII_(B) were obtained in the form of a yellow foam.

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (mt: 6H); 1.15 (d,J=6.5 Hz: 3H); 1.43 (s, 9H); from 1.35 to 2.15 (mt: 6H); 1.78 (s: 3H);2.27 (d mt, J=15 Hz: 1H); 2.77 (mt: 1H); 2.83 (dd, J=16 and 8 Hz: 1H);3.05 (dd, J=16 and 5.5 Hz: 1H); 3.55 (d, J=1.5 Hz: 1H); from 3.70 to3.95 (mt: 3H); 4.06 (broad dd, J=12 and 5 Hz: 1H); 4.15 (dd, J=14.5 and4 Hz: 1H); 4.31 (mt: 1H); 4.53 (doubled t, J=9 and 4 Hz: 1H); 4.63 (dd,J=14.5 and 9 Hz: 1H); 4.86 (dd, J=8 and 2.5 Hz: 1H); 4.91 (dd, J=10 and2 Hz: 1H); 5.19 (dd, J=10 and 1 Hz: 1H); 5.25 (dd, J=17.5 and 1 Hz:1H);5.42 (broad d, J=9 Hz: 1H); 5.66 (ddd, J=16-9 and 4 Hz: 1H); 5.91 (mt:1H); 6.31 (d, J=16 Hz: 1H); 6.92 (d, J=16 Hz: 1H); 7.02 (dd, J=16 and 4Hz: 1H); 8.14 (s: 1H).

(16R)-14-O-Allyl-16-(tert-butyldimethyl-silyloxy)-8-N-tert-butyloxycarbonyl-16-deoxo-pristinamycinII_(B) was prepared in the following manner:

0.20 cm³ of triethylamine and 0.12 g of 4-N,N-dimethylaminopyridine wereadded to a solution of 1 g of(16R)-14-O-allyl-16-(tert-butyidimethylsilyloxy)-16-deoxopristinamycinII_(B) and 3.4 g of di-tert-butyl dicarbonate in 30 cm³ ofdichloromethane, at 25° C. The reaction mixture was stirred for 16 hoursat room temperature, diluted with 30 cm³ of dichloromethane and thenpoured into 60 cm³ of saturated aqueous sodium chloride solution. Theorganic phase was separated out after settling had taken place, driedover magnesium sulphate and concentrated to dryness under reducedpressure (2.7 kPa) to give 1.65 g of a yellow oil, which was purified byflash chromatography on silica [eluent: cyclohexane/ethyl acetate (60/40by volume)]. After concentrating the fractions containing the expectedproduct, 0.71 g of(16R)-14-O-allyl-16-(tert-butyldimethylsilyloxy)-8-N-tert-butyloxycarbonyl-16-deoxopristinamycinII_(B) were obtained in the form of a thick pale yellow oil.

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.10 (s, 6H); 0.92 (s: 9H);0.96 (mt: 6H); 1.15 (d, J=6.5 Hz: 3H); 1.43 (s: 9H); from 1.50 to 2.10(mt: 7H); 1.83 (s: 3H); 2.77 (mt: 1H); 2.93 (dd, J=14.5 and 5 Hz: 1H);2.99 (dd, J=14.5 and 3 Hz: 1H); 3.77 (broad dd, J=13 and 6 Hz: 1H); 3.90(mt: 2H); 3.99 (broad dd, J=13 and 5 Hz: 1H); 4.12 (mt: 1H); from 4.25to 4.35 (mt: 2H); 4.65 (mt: 1H); 4.83 (dd, J=8 and 2.5 Hz: 1H); 4.89(dd, J=10 and 2 Hz: 1H); 5.14 (dd, J=10 and 1.5 Hz: 1H); 5.25 (dd, J=18and 1.5 Hz: 1H); 5.39 (broad d, J=9 Hz: 1H), 5.68 (ddd, J=16-9 and 4.5Hz: 1H); 5.89 (mt: 1H); 6.32 (d, J=16 Hz: 1H); 6.99 (d, J=16 Hz: 1H);7.06 (dd, J=16 and 4 Hz: 1H); 8.16 (s: 1H).

(16R)-14-O-Allyl-16-(tert-butyldimethyl-silyloxy)-16-deoxopristinamycinII_(B) was prepared in the following manner:

3.06 cm³ of diisopropylethylamine and 0.43 g of4-N,N-dimethylaminopyridine were added, at 20° C. and under an argonatmosphere, to a solution of 2 g of(16R)-14-O-allyl-16-deoxo-16-hydroxypristinamycin II_(B) and 2.64 g oftert-butyldimethylchlorosilane in 15 cm³ of dichloro-methane. Afterstirring for 17 hours, the reaction mixture was diluted with 50 cm³ ofdichloromethane and then poured into 50 cm³ of saturated aqueous sodiumchloride solution. The organic phase was separated out after settlinghad taken place, dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) to give aresidue which was stirred for 2 hours in 30 cm³ of diisopropyl ether.After filtering and drying under reduced pressure (2.7 kPa), 1.57 g of(16R)-14-O-allyl-16-(tert-butyldimethylsilyloxy)-16-deoxopristinamycinII_(B) were obtained in the form of a white powder.

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.10 (s, 6H); 0.89 (s, 9H);0.96 (d, J=6.5 Hz: 3H); 1.00 (d, J=6.5 Hz: 3H); 1.06 (d, J=6.5 Hz: 3H);1.60 (mt: 1H); from 1.75 to 2.05 (mt: 5 H); 1.82 (s: 3H); 2.16 (mt:1H);2.75 (mt:1H); 2.88 (dd, J=16 and 7.5 Hz: 1H); 2.95 (dd, J=16 and 4 Hz:1H); 3.47 (mt: 1H); 3.79 (dd, J=12 and 6 Hz: 1H); from 3.90 to 4.05 (mt:3H); 4.13 (mt: 1H); 4.25 (mt: 1H); 4.50 (mt: 1H); from 4.70 to 4.85 (mt:2H); 5.15 (dd, J=10 and 1.5 Hz: 1H); 5.19 (broad d, J=9 Hz: 1H); 5.23(dd, J=17.5 and 1.5 Hz: 1H); 5.71 (ddd, J=16-8.5 and 5 Hz: 1H); 5.81(dd, J=16.5 and 1.5 Hz: 1H); 5.88 (mt: 1H); 6.20 (d, J=16 Hz: 1H); 6.28(mt: 1H); 6.49 (dd, J=16.5 and 5 Hz: 1H); 8.05 (s: 1H).

(16R)-14-O-Allyl-16-deoxo-16-hydroxy-pristinamycin II_(B) was preparedin the following manner:

36.57 g of potassium carbonate and 65.35 cm³ of allyl bromide were addedto a solution of 20 g of (16R)-16-deoxo-16-hydroxypristinamycin II_(B)in 450 cm³ of 2-butanone, at 20° C. The reaction mixture was refluxedfor 76 hours. After cooling to 20° C. and filtering, the reactionmixture was concentrated under reduced pressure (2.7 kPa). The residuewas taken up in 200 cm³ of dichloromethane and then washed successivelytwice with 100 cm³ of water and 300 cm³ of saturated aqueous sodiumchloride solution. The organic phase was dried over magnesium sulphateand then concentrated to dryness under reduced pressure (2.7 kPa) togive 27.8 g of a yellow foam, which was purified by flash chromatographyon silica [eluent: dichloromethane/acetonitrile/methanol (94/3/3 byvolume)]. After concentrating the fractions containing the expectedproduct, 7.80 g of (16R)-14-O-allyl-16-deoxo-16-hydroxypristinamycinII_(B) were obtained in the form of a yellow foam.

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (d, J=6.5 Hz: 3H); 1.00(d, J=6.5 Hz: 3H); 1.10 (d, J=6.5 Hz: 3H); from 1.70 to 2.05 (mt: 6H);1.80 (s: 3H); 2.12 (mt: 1H); 2.74 (mt: 1H); 2.79 (dd, J=16.5 and 5.5 Hz:1H); 2.99 (dd, J=16.5 and 7 Hz: 1H); 3.15 (d, J=3 Hz: 1H); 3.42 (dd,J=16-10 and 4 Hz: 1H); from 3.80 to 3.95 (mt: 2H); from 3.95 to 4.10(mt: 2H); 4.27 (mt: 1H); from 4.45 to 4.60 (mt: 2H); 4.78 (dd, J=10 and1.5 Hz: 1H); 4.83 (dd, J=9 and 3.5 Hz: 1H); 5.18 (dd, J=10.5 and 1.5 Hz:1H); 5.25 (dd, J=18 and 1.5 Hz: 1H); 5.34 (broad d, J=9 Hz: 1H); 5.65(ddd, J=16-10 and 4.5 Hz: 1H); 5.79 (dd, J=16 and 1.5 Hz: 1H); from 5.85to 6.00 (mt: 2H); 6.22 (broad d, J=16 Hz: 1H); 6.51 (dd, J=16 and 5 Hz:1H); 8.15 (s: 1H).

(16R)-16-Deoxo-16-hydroxypristinamycin II_(B) was prepared in thefollowing manner:

A suspension of 11.35 g of sodium borohydride in 550 cm³ ofdichloromethane was refluxed for 20 minutes. 68.6 cm³ of acetic acidwere then added dropwise over about 30 minutes, followed by addition ofa solution (predried over sodium sulphate) of 52.75 g of pristinamycinII_(B) in 230 cm³ of dichloromethane, over about 45 minutes. Thereaction mixture was stirred for 4.5 hours at reflux and then for 16hours at 20° C. 500 cm³ of dichloromethane and 1500 cm³ of water werethen added to the reaction mixture. The organic phase was separated outafter settling had taken place and the aqueous phase was extracted with500 cm³ of methylene chloride. The organic phases were combined and thepH was adjusted to 8 by slow addition of 1000 cm³ of saturated aqueoussodium bicarbonate solution. The resulting organic phase was washedsuccessively with 1000 cm³ of water and 1000 cm³ of saturated aqueoussodium chloride solution and then treated with 3S vegetable charcoal,dried over sodium sulphate, filtered through Celite® and concentrated todryness under reduced pressure (2.7 kPa) to give 50 g of a pale yellowsolid. 378 cm³ of aqueous 0.5 M ammonium hydroxide solution were addedto a solution of the above solid in 900 cm³ of methylene chloride, at20° C. After stirring for 16 hours at 20° C., the organic phase wasseparated out after settling had taken place, washed with 1000 cm³ ofwater and then with 1000 cm³ of saturated aqueous sodium chloridesolution, dried over sodium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa) to give 46 g of a pale yellowsolid, which was purified by flash chromatography on silica [eluent:methylene chloride/methanol gradient (98/2 and 97/3 by volume)]. Afterconcentrating the fractions containing the expected product, 8.57 g of(16R)-16-deoxy-16-hydroxy-pristinamycin II_(B) were obtained in the formof an off-white foam melting at about 140° C. (dec.).

¹H NMR spectrum

(400 MHz, CDCl₃, δ in ppm): 0.96 (d, J=6.5 Hz: 3H); 1.00 (d, J=6.5 Hz:3H); 1.10 (d, J=6.5 Hz: 3H); from 1.70 to 2.05 (mt: 6H); 1.81 (s: 3H);from 2.05 to 2.20 (mt: 2H); 2.76 (mt: 1H); 2.84 (dd, J=16 and 5.5 Hz:1H); 3.00 (dd, J=16 and 7 Hz: 1H); 3.04 (d, J=4 Hz: 1H); 3.45 (ddd,J=16-9 and 4 Hz; 1H); 3.90 (mt: 1H); 4.04 (mt: 1H); 4.27 (mt: 1H); 4.48(ddd, J=16-9 and 4 Hz: 1H); 4.80 (dd, J=10 and 2 Hz: 1H); 4,84 (dd, J=9and 3.5 Hz: 1H); 4.88 (mt: 1H); 5.44 (broad d, J=9 Hz: 1H); 5.67 (ddd,J=16-9 and 4 Hz: 1H); 5.80 (dd, J=16 and 1.5 Hz: 1H); 5.95 (dd, J=9 and4 Hz: 1H); 6.19 (broad d, J=16 Hz: 1H); 6.53 (dd, J=16 and 5 Hz: 1H);8.16 (s: 1H).

EXAMPLE 2

(16R)-16-Deoxo-16-methoxypristinamycin II_(B)

1.2 g of sodium hydroxide, 0.50 g of tetra-n-butylammonium bromide and4.70 cm³ of iodomethane were added to a solution of 8 g of(16R)-16-deoxo-16-hydroxypristinamycin II_(B) (prepared as described inExample 1) in 40 cm³ of dichloromethane and 40 cm³ of water, at 25° C.The reaction mixture was stirred for 24 hours at room temperature andthe phases were then separated after settling had taken place. Theorganic phase was washed 3 times with 100 cm³ of saturated aqueoussodium chloride solution and then dried over magnesium sulphate,filtered and concentrated under reduced pressure (2.7 kPa) to give 10.7g of a cream-coloured foam which was purified by flash chromatography onsilica [eluent: dichloromethane/acetonitrile/methanol (95/2.5/2.5 byvolume)]. After concentrating the fractions containing the expectedproduct, 1.2 g of a pale yellow foam are obtained, which product wasrecrystallized from 7 cm³ of hot acetonitrile to give 1.15 g of(16R)-16-deoxo-16-methoxypristinamycin II_(B) in the form of whitecrystals which melted at about 125° C. (dec.).

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (d, J=6.5 Hz: 3H); 1.00(d, J=6.5 Hz: 3H); 1.08 (d, J=6.5 Hz: 3H); 1.70 (ddd, J=14-7 and 3 Hz:1H): from 1.75 to 2.05 (mt: 5H); 1.82 (s: 3H); 1.92 (d, J=4 Hz: 1H);2.14 (mt: 1H); 2.75 (mt: 1H); 2.80 (dd, J=16 and 8.5 Hz: 1H); 3.18 (dd,J=16 and 4 Hz: 1H); 3.45 (s: 3H): 3.50 (mt: 1H); 3.75 (mt: 1H); 3.95(mt: 2H); 4.45 (mt: 1H); 4.70 (mt: 1H); from 4.75 to 4.85 (mt: 2H); 5.36(broad d, J=9 Hz: 1H); 5.72 (ddd, J=16-8 and 4.5 Hz: 1H); 5.81 (dd,J=16.5 and 1.5 Hz: 1H); 6.06 (mt: 1H); 6.18 (d, J=16 Hz: 1H); 6.51 (dd,J=16.5 and 5 Hz: 1H); 8.10 (s, 1H).

EXAMPLE 3

(16R)-16-Allyloxy-16-deoxopristinamycin II_(B)

1.06 g of sodium hydroxide, 0.40 g of tetra-n-butylammonium bromide and11.49 cm³ of allyl bromide were added to a solution of 7 g of(16R)-16-deoxo-16-hydroxypristinamycin II_(B) (prepared as described inExample 1) in 50 cm³ of dichloromethane and 50 cm³ of water, at 25° C.The reaction mixture was stirred for 24 hours at room temperature andthe phases were then separated once settling had taken place. Theorganic phase was washed twice with 100 cm³ of saturated aqueous sodiumchloride solution and then dried over magnesium sulphate, filtered andconcentrated under reduced pressure (2.7 kPa) to give 7.15 g of a yellowfoam, which was purified by flash chromatography on silica [eluent:dichloromethane/acetonitrile/methanol (95/2.5/2.5 by volume)]. Afterconcentrating the fractions containing the expected product, 1.2 g of awhite foam were obtained, which product was recrystallized from 5 cm³ ofhot acetonitrile to give 0.68 g of(16R)-16-allyloxy-16-deoxopristinamycin II_(B) in the form of whitecrystals which melted at about 114° C. (dec.).

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (d, J=6.5 Hz: 3H); 1.00(d, J=6.5 Hz: 3H); 1.08 (d, J=6.5 Hz: 3H); 1.73 (ddd, J=15-7.5 and 5 and3 Hz: 1H); from 1.75 to 2.05 (mt: 5H); 1.81 (s: 3H); 2.14 (mt: 1 H);2.74 (mt: 1H); 2.82 (dd, J=16 and 8.5 Hz: 1H); 3.16 (dd, J=16 and 3.5Hz: 1H); 3.50 (ddd, J=16-8.5 and 3.5 Hz: 1H); 3.91 (mt: 1H); 3.94 (mt:2H); 4.00 (resolved dd, J=12.5 and 5.5 Hz: 1H); 4.17 (resolved dd,J=12.5 and 5.5 Hz: 1H); 4.45 (ddd, J=16-9 and 5 Hz: 1H); 4.71 (mt: 1H);4.76 (dd, J=9 and 3.5 Hz: 1H); 4.78 (dd, J=10 and 1.5 Hz: 1H); 5.22 (dd,J=10 and 1.5 Hz: 1H); 5.32 (dd, J=17.5 and 1.5 Hz: 1H); 5.35 (broad d,J=9 Hz: 1H);5.73 (ddd, J=16-8.5 and 5 Hz: 1H); 5.81 (dd, J=16 and 1.5Hz: 1H); 5.96 (mt: 1H); 6.11 (mt: 1H); 6.17 (broad d, J=16 Hz: 1H); 6.51(dd, J=16 and 5 Hz: 1H); 8.08 (s: 1H).

EXAMPLE 4

(16R)-16-Deoxo-16-(prop-2-ynyloxy)pristinamycin II_(B)

Working in a similar manner to that described in Example 2, but startingwith 7 g of (16R)-16-deoxo-16-hydroxypristinamycin II_(B) dissolved in40 cm³ of dichloromethane, 1.7 g of tetra-n-butylammonium bromide, 1.06g of sodium hydroxide, 40 cm³ of water and 5 cm³ of propargyl bromidewere added, at 20° C. and under an argon atmosphere. After stirring for18 hours and work-up, 7.23 g of an orange solid were obtained, whichproduct was purified by flash chromatography on silica [eluent:dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. Afterconcentrating the fractions containing the expected product, 1.58 g of ayellow solid were obtained, which product was recrystallized from 40 cm³of hot acetonitrile. After filtering off the crystals through a No. 4sinter funnel with 40 cm³ of acetonitrile and drying under reducedpressure (2.7 kPa), 1.36 g of(16R)-16-deoxo-16-(prop-2-ynyloxy)pristinamycin II_(B) were obtained inthe form of white crystals which melted at about 112° C. withdecomposition.

¹H NMR spectrum (400 MHz, CDCl₃, δ in ppm): 0.96 (d, J=6.5 HZ: 3H); 1.01(d, J=6.5 Hz: 3H); 1.08 (d, J=6.5 Hz: 3H); 1.75 (ddd, J=16-7.5 and 3.5Hz; 1H); from 1.75 to 2.05 (mt: 5H); 1.84 (s: 3H); 1.85 (d, J=3.5 Hz:1H); 2.15 (mt: 1H); 2.48 (t, J=2.5 Hz: 1H); 2.75 (mt: 1H); 2.87 (dd,J=16 and 9 Hz: 1H); 3.21 (dd, J=16 and 3.5 Hz: 1H); 3.50 (ddd, J=16-8and 3.5 Hz: 1H); 3.94 (mt: 2H); 4.09 (mt: 1H); 4.25 (dd, J=16 and 2.5Hz: 1H); 4.31 (dd, J=16 and 2.5 Hz: 1H); 4.46 (mt: 1H); from 4.65 to4.80 (mt: 2H); 4.78 (dd, J=10 and 1.5 Hz: 1H); 5.36 (broad d, J=9 Hz:1H); 5.74 (ddd, J=16-8.5 and 5 Hz: 1H); 5.82 (dd, J=16 and 1.5 Hz: 1H);from 6.10 to 6.25 (mt: 1H); 6.18 (broad d, J=16 Hz: 1H); 6.51 (dd, J=16and 5.5 Hz: 1H); 8.10 (s, 1H).

EXAMPLE 5

(16R)-16-Deoxo-16-methoxypristinamycin II_(A)

Working in a manner similar to that described in Example 2, but startingwith a solution of 8 g of (16R)-16-deoxo-16-hydroxypristinamycin II_(A)in 40 cm³ of dichloromethane and 40 cm³ of water, 1.2 g of sodiumhydroxide, 0.49 g of tetra-n-butylammonium bromide and 4.7 cm³ of methyliodide were added, at 25° C. After stirring for 96 hours and work-up,and after purification by flash chromatography on silica [eluent:dichloromethane/acetonitrile/methanol (96/2/2 by volume)] andconcentrating the fractions containing the expected product, 0.38 g of afoam was obtained, which was diluted in 40 cm³ of ethyl acetate and thenwashed successively with 20 cm³ of 0.1 N hydrochloric acid solution, 20cm³ of water and 20 cm³ of saturated aqueous sodium chloride solution.The organic phase was dried over magnesium sulphate, filtered andconcentrated under reduced pressure (2.7 kPa) to give 0.15 g of(16R)-16-deoxo-16-methoxypristinamycin II_(A) in the form of a whitepowder which melted at about 151° C. with decomposition.

¹H NMR spectrum (300 MHz, CDCl₃, δ in ppm): 0.98 (d, J=6.5 Hz: 3H); 1.00(d, J=6.5 Hz: 3H); 1.13 (d, J=6.5 Hz: 3H); 1.50 (d, J=3.5 Hz: 1H); 1.75(d, J=1 Hz: 3H); 1.88 (ddd, J=16-10.5 and 3 Hz: 1H); from 1.95 to 2.10(mt: 2H); from 2.60 to 2.90 (mt: 4H); 3.14 (dd, J=14 and 3 Hz: 1H); 3.26(mt: 1H); 3.44 (s: 3H); 3.87 (very broad d, J=17 Hz: 1H); from 4.15 to4.45 (mt: 3H); 4.53 (mt: 1H); 4.86 (broad d, J=9 Hz: 1H); 4.96 (dd, J=10and 2 Hz: 1H); 5.66 (ddd, J=16-5 and 3.5 Hz: 1H); 5.93 (broad d, J=16Hz: 1H); 6.02 (dd, J=16.5 and 1 Hz: 1H); 6.14 (t, J=3 Hz: 1H); 6.62 (dd,J=16.5 and 7.5 Hz: 1H); from 7.25 to 7.40 (mf: 1H); 7.89 (s, 1H).

(16R)-16-Hydroxypristinamycin II_(A) may be prepared, for example,according to F. Le Goffic et. al., Transformations of Pristinamycin IIto Study Its Mechanism of Action, 16(1) Eur. J. Medicinal Chemistry 69(January-February 1981).

The present invention also relates to pharmaceutical compositionscomprising at least one streptogramin group A derivative according tothe invention, in pure form, combined with at least one group Bstreptogramin derivative, where appropriate in the form of a salt,and/or in the form of a combination with at least one compatible andpharmaceutically acceptable diluent or adjuvant.

The compositions according to the invention may be used, for example,orally, parenterally, topically, rectally or as aerosols.

Solid compositions for oral administration which may be used include,for example, tablets, pills, gel capsules, powders and granules. Inthese compositions, the active product according to the invention,generally in the form of a combination, can be mixed with at least oneinert diluent or adjuvant, such as, for example, sucrose, lactose orstarch. These compositions may comprise substances other than diluents,for example, a lubricant such as magnesium stearate or a coatingintended for controlled release.

Liquid compositions for oral administration which may be used include,for example, pharmaceutically acceptable solutions, suspensions,emulsions, syrups and elixirs containing inert diluents such as water orliquid paraffin. These compositions may also comprise substances otherthan diluents, such as, for example, wetting, sweetening or flavoringproducts.

The compositions for parenteral administration may be, for example,sterile solutions or emulsions. Solvents or vehicles which may be usedinclude, for example, propylene glycol, polyethylene glycol, plant oils,such as, for example, olive oil, and injectable organic esters, forexample, ethyl oleate. These compositions may also comprise at least oneadjuvant, such as, for example, adjuvants chosen from wetting agents,isotonic agents, emulsifiers, dispersants, and stabilizers.

The sterilization may be carried out in several ways, for example, usinga bacteriological filter, by irradiation, or by heating. Thecompositions may also be prepared in the form of sterile solidcompositions which may be dissolved at the time of use in sterile wateror any other injectable sterile medium.

The compositions for topical administration may be, for example, in theform of creams, ointments, lotions or aerosols.

The compositions for rectal administration may be, for example,suppositories or rectal capsules which contain, besides the activeprinciple, excipients such as cocoa butter, semisynthetic glycerides orpolyethylene glycols.

The compositions may also be aerosols. For use in the form of liquidaerosols, the compositions may be stable sterile solutions or solidcompositions dissolved at the time of use in apyrogenic sterile water,in saline or any other pharmaceutically acceptable vehicle. For use inthe form of dry aerosols for direct inhalation, the active principle wasfinely divided and combined with a solid water-soluble diluent orvehicle with a particle size ranging, for example, from 30 to 80 μm, forexample, dextran, mannitol or lactose.

In human therapy, for example, the novel streptogramin derivativesaccording to the invention can be used for treating infections ofbacterial origin. The doses depend on the desired effect and theduration of the treatment. The doctor will determine the dosage (s)heconsiders to be most suitable depending on the treatment, as a functionof the age, weight, degree of infection and the other factors specificto the individual to be treated. Generally, for example, the doses canrange from 0.5 to 3 g of active product in 2 or 3 administrations perday, via the oral or parenteral route for an adult.

The example which follows illustrates a composition according to theinvention, without however exhibiting a limiting character.

EXAMPLE

Tablets containing a 250 mg dose of active product and having thecomposition below can be prepared according to known, art-recognizedtechniques:

(16R)-16-Deoxo-16-methoxy-pristinamycin II_(B) 175 mg PristinamycinI_(B)  75 mg Excipient: starch, hydrated silica, dextrin, 500 mggelatin, magnesium stearate: qs

1. A pharmaceutical composition comprising at least one group Astreptogramin compound of formula (I) or a salt thereof:

wherein: R₁ is chosen from alkyl groups, alkenyl groups, alkynyl groups,monofluoro substituted alkyl groups, monofluoro substituted alkenylgroups, monofluoro substituted alkynyl groups, polyfluoro substitutedalkyl groups, polyfluoro substituted alkenyl groups, polyfluorosubstituted alkynyl groups, C₃-C₆ cycloalkyl groups, a phenylmethylgroup, and heterocyclylmethyl groups, wherein said heterocyclyl portionis aromatic, R₂ is chosen from a hydrogen atom, a methyl group, and anethyl group, the bond

is a single bond (27R stereochemistry) or a double bond, unlessotherwise stated, said alkyl groups are chosen from straight andbranched C₁-C₆alkyl groups, unless otherwise stated, said alkenyl groupsare chosen from straight and branched C₃-C₆ alkenyl groups, and unlessotherwise stated, said alkynyl groups are chosen from straight andbranched C₃-C₆ alkynyl groups, and at least one group streptogramincompound or salt thereof, and wherein said at least one group Bstreptogramin compound or salt thereof is chosen from semi-syntheticcompounds of formula (A) and salts thereof:

 wherein: (1) Rb, Rc, Re, and Rf are each a hydrogen atom; Rd is chosenfrom a hydrogen atom and a dimethylamino group; and Ra is chosen from:(A) —CH₂R′a groups, wherein R′a is chosen from: (i) apyrrolidinyl-3-thio group, (ii) a piperidyl-3-thio group, (iii) apiperidyl-4-thio group, wherein said groups (i)-(iii) may beunsubstituted or substituted with at least on group chosen from alkylgroups, and (iv) alkylthio groups which are substituted with 1 or 2groups chosen from: (a) a hydroxysulfonyl group, (b) alkylamino groups,(c) dialkylamino groups, which may be unsubstituted or substituted withat least one group chosen from a mercapto group or dialkylamino groups,(d) a piperazine ring, a morpholino group, a thiomorpholino group, apiperidino group, a 1-pyrrolidinyl group, a 2-piperidyl group, a3-piperidyl group, a 4-piperidyl group, a 2-pyrrolidinyl group, and a3-pyrrolidinyl group, each of which may be unsubstituted or substitutedwith alkyl, and (B) ═CHR′a groups, wherein R′a is chosen from: (i) apyrrolidinyl-3-amino group, (ii) a piperidyl-3-amino group and apiperidyl-4-amino group, (iii) a pyrrolidinyl-3-oxy group, (iv) apiperidyl-3-oxy group and a piperidyl-4-oxy group, (v) apyrrolidinyl-3-thio group, (vi) a piperidyl-3-thio group and apiperidyl-4-thio group, wherein said groups (i)-(vi) may beunsubstituted or substituted with at least one group chosen from alkylgroups, (vii) alkylamino groups, (viii) alkyloxy groups, and (ix)alkylthio groups, wherein said groups (vii), (viii), and (ix) aresubstituted with 1 or 2 groups chosen from: (a) hydroxysulfonyl group,(b) alkylamino groups, (c) dialkylamino groups unsubstituted orsubstituted with at least one group chosen from dialkylamino groups, (d)trialkylammonio groups, (e) a 4-imidazolyl group, and a 5-imidazolylgroup, each of which may be unsubstituted or substituted with alkyl, (f)piperazine ring, a morpholino group, a thiomorpholino group, apiperidino group, a 1-pyrrolidinyl group, a 2-piperidyl group, a3-piperidyl group, a 4-piperidyl group, a 2-pyrrolidinyl group, and a3-pyrrolidinyl group, each of which may be unsubstituted or substitutedwith alkyl, (C) a quinuclidinyl-3-thiomethyl group, and (D) aquinuclidinyl-4-thiomethyl group; or Ra is a hydrogen atom, and (a) Rb,Re, and Rf are each a hydrogen atom, and Rd is chosen from a —NHCH₃group and a —N(CH₃)₂ group, and Rc is chosen from a chlorine atom and abromine atom, or when Rd is a —N(CH₃)₂ group, Rc is chosen from (C₃-C₅)alkenyl groups, or (b) Rb, Rd, Re, an Rf are each a hydrogen atom, andRc is chosen fr m halogen atoms, aminomonoalkyl groups, aminodialkylgroups, alkyloxy groups, a trifluoromethyloxy group, thioalkyl groups,C₁-C₃) alkyl groups, and trihalomethyl groups, or (c) Rb, Rc, Re, an Rfare each a hydrogen atom, and Rd is chosen from halogen atoms, anethylamino group, a diethylamino group, a methylethylamino group,alkyloxy groups, a trifluoromethyloxy group, thioalkyl groups, (C₁-C₆)alkyl groups, aryl groups, and trihalomethyl groups, or (d) Rb, Re, andRf are each a hydrogen atom, Rc is chosen from halogen atoms,aminomonoalkyl groups, aminodialkyl groups, alkyloxy groups, atrifluoromethyloxy group, thioalkyl groups, and (C₁-C₃) alkyl groups,and Rd is chosen from halogen atoms, an amino group, aminomonoalkylgroups, aminodialkyl groups, alkyloxy groups, a trifluoromethyloxygroup, thioalkyl groups, (C₁-C₆) alkyl groups, and trihalomethyl groups,or (e) Rc, Re, and Rf are each a hydrogen atom, and Rb and Rd are each amethyl group.
 2. A pharmaceutical composition comprising at least onegroup A streptogramin compound of formula (I) or a salt thereof:

wherein R₁ is chosen from alkyl groups, alkenyl groups, alkynyl groups,monofluoro substituted alkyl groups, monofluoro substituted alkenylgroups, monofluoro substituted alkynyl groups, polyfluoro substitutedalkyl groups, polyfluoro substituted alkenyl groups, polyfluorosubstituted alkynyl groups C₃-C₆ cycloalkyl groups, a phenylmethylgroup, and heterocyclylmethyl groups, wherein said heterocyclyl portionis aromatic, R₂ is chosen from a Hydrogen atom, a methyl group, and anethyl group, the bond

is a single bond (27R stereochemistry) or a double bond, unlessotherwise stated, said alkyl groups are chosen from straight andbranched C₁-C₆ alkyl groups, unless otherwise stated, said alkenylgroups are chosen from straight and branched C₃-C₆ alkenyl groups, andunless otherwise stated said alkynyl groups are chosen from straight andbranched C₃-C₆ alkynyl groups, and at least one group streptogramincompound or salt thereof, and wherein said at least one group Bstreptogramin compound or salt thereof is chosen from semisyntheticcompounds of formula (B) and salts thereof:

 wherein: (A) Y is chosen from (i) a nitrogen atom and (ii) ═CR₃-groups,and (1) when Y is chosen from ═CR₃-groups, R₁ is chosen from (a₁) ahydrogen atom, C₁-C₈ alkyl groups, and C₂-C₈ alkenyl groups, (b₁) C₃-C₈cycloalkyl groups, and saturated and unsaturated 3- to 8-memberedheterocyclyl groups, (c₁) an unsubstituted phenyl group, (d₁) a phenylgroup substituted with at least one substituent chosen from halogenatoms, a hydroxyl group, alkyl groups, alkyloxy groups, alkylthiogroups, alkylsulphinyl groups, alkylsulphonyl groups, an amino groupalkylamino groups, and dialkylamino groups, and (e₁) groups —NR′R″,wherein: R′ and R″, which are identical or different, are each chosenfrom a hydrogen atom, and C₁-C₃ alkyl groups, or R′ and R″, form,together with the nitrogen atom to which they are attached, a 3- to8-membered heterocyclyl group, wherein one of said members, in additionto said nitrogen atom, may be a heteroatom chosen from an oxygen atom, asulphur atom, and a nitrogen atom, and wherein said heterocyclyl groupis unsubstituted or substituted with a group chose from alkyl groups,C₂-C₈ alkenyl groups, C₃-C₆ cycloalkyl groups, saturated and unsaturated4- to 6-membered heterocyclyl groups, a benzyl group, an unsubstitutedphenyl group, and a substitute phenyl group, as defined above in (d₁),(f₁) halomethyl groups, a hydroxymethyl group, and alkyloxymethylgroups, (g₁) alkylthiomethyl groups, wherein said alkyl portion isunsubstituted or substituted with an —NR′R″ group, and wherein said R′and said R″ are as defined above in (e₁), (h₁) alkylsulphinylmethylgroups, alkylsulphonylmethyl groups, an acyloxymethyl group, abenzoyloxymethyl group, a cyclopropylaminomethyl group, and—(CH₂)_(n)NR′R″ groups, wherein n is chosen from integers ranging from 1to 4, and wherein said R′ and said R″ are defined above in (e₁), and(i₁) when R₃ is hydrogen atom, R₁ is additionally chosen from a formylgroup, a carboxyl group, alkyloxycarbonyl groups, and —CONR′R″ groups,wherein said R′ and said R″ are defined as above in (e₁), and (2) when Yis a nitrogen atom, R₁ is chosen from (a₂) options (a₁), (b₁), (c₁),(d₁), and (e1) as defined above, and (b₂) ) XR^(o) groups, wherein X ischosen from an oxygen atom, a sulphur atom, a sulphinyl group, asulphonyl group, and an —NH— group, and wherein R^(o) is chosen from (i)(C₁ to C₈) alkyl groups, (ii) (C₃ to C₆) cycloalkyl groups, (iii)saturated and unsaturated 3- to 8-membered heterocyclyl groups, (iv) 3-to 8-membered heterocyclylmethyl groups in which the heterocyclylportion is attached to the methyl group by a carbon atom (v) anunsubstituted phenyl group, (vi) phenyl groups substituted with at leastone group chosen from halogen atoms, a hydroxyl group, alkyl groups,alkyloxy groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonylgroups, an amino group, alkylamino groups, and dialkylamino groups,(vii) —(CH₂)_(n)NR′R″ groups, wherein R′ and R″ are as defined above in(e₁), and wherein n is chosen from integers ranging from 2 to 4, and(viii) if X is an NH group, R^(o) may also be a hydrogen atom; (B) R₂ ischosen from a hydrogen atom and C₁-C₃ alkyl groups, (C) R₃ is chosenfrom a hydrogen atom, alkyl groups, a carboxyl group, alkyloxycarbonylgroups, and carbamoyl groups of formula —CO—NR′R″, wherein said R′ andsaid R″ are defined as above in (e₁), (D) Ra is chosen in a methyl groupand an ethyl group, and (E) Rb, Rc, and Rd are defined as follows: (1)Rb and Rc are each a hydrogen atom and Rd is chosen from a hydrogenatom, a methylamino group, and a dimethylamino group, or (2) Rb is ahydrogen atom, Rc is chosen from a hydrogen atom, a chlorine atom, abromine atom, and C₃-C₅ alkenyl groups, and Rd is chosen from —N(CH₃)R′″groups, wherein R′″ is chosen from (a) alkyl groups, (b) C₂-C₄hydroxyalkyl groups, (c) C₂-C₈ alkenyl groups, wherein said C₂-C₈alkenyl groups are unsubstituted d or substituted with (i) anunsubstituted phenyl group, (ii) a cycloalkyl(C₃-C₆)methyl group, (iii)an unsubstituted benzyl group, (iv) benzyl group substituted with atleast one substituent chosen from halogen atoms, a hydroxyl group, alkylgroups, alkyloxy groups, alkylthio groups, alkylsulphinyl groups,alkylsulphonyl groups, an amino group, alkylamino groups, anddialkylamino groups, or (v) heterocyclylmethyl groups andheterocyclylethyl groups, wherein said heterocyclyl portions of saidheterocyclylmethyl groups and said heterocyclylethyl groups are chosenfrom saturated and unsaturated 5- to 6-membered heterocyclyl groupscomprising from 1 to 2 heteroatoms chosen from a sulphur atom, an oxygenatom, and a nitrogen atom, and wherein said heterocyclyl groups may beunsubstituted or substituted with a group chosen from alkyl groups,C₂-C₈ alkenyl groups, C₃-C₆ cycloalkyl groups, saturated and unsaturated4- to 6-membered heterocyclyl groups, an unsubstituted phenyl group, abenzyl group, or a substituted phenyl group as defined above in (d₁),(d) a cyanomethyl group, (e) —CH₂CORe groups, wherein Re is chosen from(i) —OR′e groups, wherein R′e is chosen from a hydrogen atom, C₁-C₆alkyl groups, C₂-C₆ alkenyl groups, a benzyl group, andheterocyclylmethyl groups, wherein said heterocyclyl portion is chosenfrom 5- to 6-membered heterocyclyl groups comprising from 1 to 2heteroatoms chosen from a sulphur atom, an oxygen atom, and a nitrogenatom, (ii) alkylamino groups, alkylmethylamino groups, heterocyclylaminogroups and heterocyclylmethylamino groups, wherein said heterocyclylportion of said heterocyclylamino groups and saidheterocyclylmethylamino groups is chosen from 5- to 6-membered saturatedheterocyclyl groups comprising from 1 to 2 heteroatoms chosen from asulphur atom, an oxygen atom, and a nitrogen atom, and wherein saidheterocyclyl groups may be unsubstituted or substituted with a groupchosen from alkyl groups, a benzyl group, and alkyloxycarbonyl groups,or (3) Rb is a hydrogen atom, Rd is chosen from an —NHCH₃ group and an—N(CH₃)₂ group, and Rc is chosen from a chlorine atom, and a bromineatom, and when Rd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅ alkenylgroups, or (4) Rb and Rd are each a hydrogen atom, and Rc is chosen fromhalogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups,a trifluoromethoxy group, thioalkyl groups, C₁-C₆ alkyl groups andtrihalomethyl groups, or (5) Rb and Rc are each a hydrogen atom, and Rdis chosen from halogen atoms, an ethylamino group, a diethylamino group,a methylethylamino group, alkyloxy groups, a trifluoromethoxy group,alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, C₁-C₆alkyl groups, a phenyl group, and trihalomethyl groups, or (6) Rb is ahydrog n atom, and Rc is chosen from halogen atoms, alkylamino groups,dialkylamino groups, alkyloxy groups, a trifluoromethoxy group,thioalkyl groups, and C₁-C₃ alkyl groups, and Rd is chosen from halogenatoms, an amino group, alkylamino groups, dialkylamino groups, alkyloxygroups, a trifluoromethoxy group, thioalkyl groups, C₁-C₆ alkyl groups,and trihalomethyl groups, or (7) Rc is a hydrogen atom, and Rb and Rdare each a methyl group.
 3. A pharmaceutical composition comprising atleast one group A streptogramin compound of formula (I) or a saltthereof:

wherein: R₁ is chosen from alkyl groups, alkenyl groups, alkynyl groups,monofluoro substituted alkyl groups, monofluoro substituted alkenylgroups, monofluoro substituted alkynyl groups, polyfluoro substitutedalkyl groups, polyfluoro substituted alkenyl groups, polyfluorosubstituted alkynyl groups, C₃-C₆ cycloalkyl groups, a phenylmethylgroup, and heterocyclylmethyl groups, wherein said heterocyclyl portionis aromatic, R₂ is chosen from a hydrogen atom, a methyl group, and anethyl group, the bond

is a single bond (27R stereochemistry) or a double bond, unlessotherwise stated, said alkyl groups are chosen from straight andbranched C₁-C₆ alkyl groups, unless otherwise stated, said alkenylgroups are chosen from straight and branched C₃-C₆ alkenyl groups, andunless otherwise stated, said alkynyl groups are chosen from straightand branched C₃-C₆ alkynyl groups, and at least one group Bstreptogramin compound or salt thereof, and wherein said at least onegroup B streptogramin compound or salt thereof is chosen fromsemisynthetic compounds of formula (C) and salts thereof:

 wherein: (A) R is chosen from (1) NR₁R₂ groups, wherein R₁ and R_(2,)which may be identical or different, are each chosen from (i) a hydrogenatom, (ii) (C₁-C₈) alkyl groups, (iii) (C₁-C₈) alkyl groups substitutedwith a hydroxyl group, (iv) (C₃-C₈) alkenyl groups, (v) (C₃-C₈)cycloalkyl groups, (vi) (C₁-C₈) alkyloxy groups, (vii) dialkylaminogroups, (viii) phenylalkyl groups, (ix) phenylalkyl groups substitutedwith at least one group chosen from halogen atoms, alkyl groups,hydroxyalkyl groups, alkyloxy groups, and dialkylamino groups, and (x)3- to 8-member saturated and unsaturated heterocyclylalkyl groupscomprising at least one hetero atom chosen from nitrogen, oxygen, andsulphur, or (xi) R₁ and R₂ form together with the nitrogen atom to whichthey are attached, a saturated, partially saturated or unsaturated mono-or polycyclic 3- to 12-membered heterocycle group, wherein one of saidmembers, in addition to said nitrogen atom, may be an atom chosen fromoxygen sulphur, and nitrogen, and wherein said heterocyclyl group isunsubstituted or substituted with at least one group chosen from ahydroxyl group, alkyl groups, an unsubstituted phenyl group, a phenylgroup substituted with a halogen atom, phenylalkyl groups,phenyl(C₂-C₄)alkenyl groups, hydroxyalkyl groups, acyl groups,alkyloxycarbonyl groups, heterocyclyl groups and heterocyclylcarbonylgroups, wherein the heterocyclyl portion is saturated or unsaturated(4-to 6-membered) and comprises at least one hetero atom chosen fromnitrogen, sulphur, and oxygen, and (2) —SR₃ groups, where in R₃ ischosen from (i) (C₁-C₈) alkyl groups and(C₃-C₈) cycloalkyl groupssubstituted with —NR₁R₂, wherein R₁ and R_(2,) which may be identical ordifferent, are each chosen from a hydrogen atom and alkyl groups, orform, together with the nitrogen atom to which they are attached, aheterocycle as defined above in (xi), and (ii) saturated and saturatedheterocyclyl and heterocyclylmethyl (3- to 7-membered) groups, whereinone of said members, in addition to said nitrogen atom, may be an atomchosen from oxygen, sulphur, and nitrogen, an wherein said heterocyclylportion is unsubstituted or substituted with an alkyl group, (B)

 is a residue of an unsaturated ring which is not substituted in the 5γposition

 or the residue of a saturated ring which is substituted in the 5γposition with a fluorine atom

(C) Ra is chosen from a methyl group and an ethyl group, and (D) Rb, Rcand Rd ar defined below: 1) Rb and Rc are each a hydrogen atom, and Rdis chosen from a hydrogen atom, a methylamino group, and a dimethylaminogroup, or 2) Rb is a hydrogen atom, Rc is chosen from a hydrogen atom, achlorine atom, a bromine atom, and a (C₃ to C₅) alkenyl group, and Rd is—N(CH₃)—R′″, wherein R′″ is chosen from: (1) alkyl groups, (2) (C₂ toC₄) hydroxyalkyl groups, (3) (C₂ to C₈) alkenyl groups, (4)phenylalkenyl groups, (5) cycloalkyl(C₃ to C₆)methyl groups, (6) anunsubstituted benzyl group, (7) a substituted benzyl group, (8)heterocyclylmethyl groups and heterocyclylethyl groups, (9) —CH₂CNgroup, (10) a —CH₂COOH group, and (11) —CORe groups and —CH₂CORe groupsfor which either: (a) Re is —OR′e, wherein R′e is chosen from a hydrogenatom, C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, a benzyl group, andheterocyclylmethyl groups, wherein said heterocyclyl portion is chosenfrom 5- to 6-membered heterocyclyl groups comprising from 1 to 2heteroatoms chosen from a sulphur atom, an oxygen atom , and a nitrogenatom, or (b) Re is chosen from alkylamino groups, alkylmethylaminogroups, heterocyclylamino groups, and heterocyclylmethylamino groups, or3) Rb is a hydrogen atom, Rd is chosen from an —NHCH₃ group and an—N(CH₃)₂ group, and Rc is chosen from a chlorine atom, and a bromineatom, and when Rd is an —N(CH₃)₂ group, Rc is chosen from C₃-C₅ alkenylgroups, or 4) Rb and Rd are each a hydrogen atom, and Rc is chosen fromhalogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups,trifluoromethoxy group, thioalkyl groups, (C₁-C₆) alkyl groups, andtrihalomethyl groups, or 5) Rb and Rc are each a hydrogen atom, and Rdis chosen from halogen atoms, an ethylamino group, a diethylamino group,a methylethylamino group, alkyloxy groups, a trifluoromethoxy group,alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, (C₁-C₆)alkyl groups, a phenyl group, and trihalomethyl groups, or 6) Rb is ahydrogen atom, Rc is chosen from halogen atoms, alkylamino groups,dialkylamino groups, alkyloxy groups, trifluoromethoxy group, thioalkylgroups, (C₁-C₃) alkyl groups, and Rd is chosen from halogen atoms, anamino group, alkylamino groups, dialkylamino groups, alkyloxy groups, atrifluoromethoxy group, thioalkyl groups, (C₁-C₆) alkyl groups, andtrihalomethyl groups, or 7) Rc is a hydrogen atom, and Rb and Rd areeach a ethyl group.
 4. A pharmaceutical composition according to any oneof claims 1 to 3, wherein said at least one group B streptogramincompound or salt thereof is chosen from pristinamycin IA, pristinamycinIB, pristinamycin IC, pristinainycin ID, pristinamycin IE, pristinamycinIF, pristinamycin IG, virginiamycin S1, virginiamycin S3, virginiamycinS4, vernamycin B, vernamycin C, and etamycin.